The vanilloid receptor-1 (VR1, or transient receptor potential vanilloid-1, TRPV1) is the receptor for capsaicin (8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient in hot peppers. The molecular cloning of TRPV1 was reported in 1997 (Caterina et al., 1997, Nature, 389, pp 816-824), which belongs to the TRP channel family of non-selective cation channel. TRPV1 is activated or sensitized by stimuli such as capsaicin, resiniferatoxin, heat, acid, anandamide, lipid metabolites or the like; thus it plays a crucial role as a molecular integrator of noxious stimuli in mammals (Tominaga et al., 1998, Neuron, 21 pp 531-543; Hwang et al., 2000, PNAS, 97, pp 6155-6160). The TRPV1 is highly expressed in primary afferent sensory neurons, and also reportedly expressed in various organs and tissues such as bladder, kidney, lung, intestine, skin, central nervous system (CNS), and non-neuronal tissues (Mezey et al., 2000, PNAS, 97, pp 3655-3660; Stander et al., 2004, Exp. Dermatol. 13, pp 129-139; Cortright et al., 2001, BBRC, 281, pp 1183-1189), and besides TRPV1 protein is upregulated in painful disease conditions. Activation of the TRPV1 by endogenous/exogenous stimuli leads to not only transmission of noxious stimuli, but also liberation of neuropeptides such as substance P, CGRP (Calcitonin Gene-Related Peptide) in the neurons, thereby causing neurogenic inflammation. TRPV1 knock-out mice show normal responses in a wide range of behavioural tests including noxious mechanical and acute thermal stimuli, but exhibit little thermal hypersensitivity in inflammation states. (Caterina et al., 2000, Science, 288, pp 306-313; Davis et al., 2000, Nature, 405, pp 183-187; Karai et al., 2004, J. Clin. Invest., 113, pp 1344-1352).
As mentioned above, the TRPV1 knock-out mice exhibit reduced responses to thermal or noxious stimuli, which has been supported by the effects of TRPV1 antagonists in various animal models of pain (Immke et al., 2006, Semin. Cell. Dev. Biol., 17(5), pp 582-91; Ma et al., 2007, Expert Opin. Ther. Targets, 11(3), pp 307-20). The well-known TRPV1 antagonist, capsazepine, decreases hyperalgesia caused by physical stimuli in several models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp 56-62; Garcia-Martinez et al., 2002, PNAS, 99, 2374-2379). In addition, treatment of the primary culture of afferent sensory neurons with the TRPV1 agonist, capsaicin etc., results in damage to nerve functions and furthermore death of nerve cells. The TRPV1 antagonist exerts defense actions against such damage to nerve functions and nerve cell death (Holzer P., 1991, Pharmacological Reviews, 43, pp 143-201; Mezey et al., 2000, PNAS, 97, 3655-3660). The TRPV1 is expressed on sensory neurons distributed in all regions of the gastrointestinal tract and is highly expressed in inflammatory disorders such as irritable bowel syndrome and inflammatory bowel disease (Chan et al., 2003, Lancet, 361, pp 385-391; Yiangou et al., 2001, Lancet, 357, pp 1338-1339). In addition, activation of the TRPV1 stimulates sensory nerves, which in turn causes release of neuropeptides which are known to play a critical role in pathogenesis of gastrointestinal disorders such as gastro-esophageal reflux disease (GERD) and stomach duodenal ulcer (Holzer P., 2004, Eur. J. Pharmacol. 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320).
The TRPV1-expressing afferent nerves are abundantly distributed in airway mucosa, and bronchial hypersensitivity is very similar mechanism to hyperalgesia. Protons and lipoxygenase products, known as endogenous ligands for the TRPV1, are well known as crucial factors responsible for development of asthma and chronic obstructive pulmonary diseases (Hwang et al., 2002, Curr. Opin. Pharmacol. pp 235-242; Spina et al., 2002, Curr. Opin. Pharmacol. pp 264-272). Moreover, it has been reported that air-polluting substances which are a kind of asthma-causing substances, i.e., particulate matter specifically acts on the TRPV1 and such action is inhibited by capsazepine (Veronesi et al., 2001, NeuroToxicology, 22, pp 795-810). Urinary bladder hypersensitiveness and urinary incontinence are caused by various central/peripheral nerve disorders or injury, and TRPV1 expressed in afferent nerves and urothelial cells play an important role in bladder inflammation. (Birder et al., 2001, PNAS, 98, pp 13396-13401). Further, TRPV1 knock-out mice are anatomically normal but have higher frequency of low-amplitude, non-voiding bladder contractions and reduced reflex voiding during bladder filling as compared to wild type mice, which is thus indicating that the TRPV1 affects functions of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp 856-860). The TRPV1 is distributed in human epidermal keratinocytes as well as in primary afferent sensory nerves (Denda et al., 2001, Biochem. Biophys. Res. Commun, 285, pp 1250-1252; Inoue et al., 2002, Biochem. Biophys. Res. Commun., 291, pp 124-129), and it is then involved in transmission of various noxious stimuli and pains such as skin irritation and pruritus, thereby having close correlation with etiology of dermatological diseases and disorders, such as skin inflammation, due to neurogenic/non-neurogenic factors. This is supported by the report that the TRPV1 antagonist, capsazepine inhibits inflammatory mediators in human skin cells (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 217-222). Over recent years, evidence has been accumulation on other roles of TRPV1. TRPV1 might be involved in the blood flow/pressure regulation via sensory vasoactive neuropeptide release and in the regulation of plasma glucose levels or in the pathogenesis of type 1 diabetes (Inoue et al., Cir. Res., 2006, 99, pp 119-31; Razavi et al., 2006, Cell, 127, pp 1123-35; Gram et al., 2007, Eur. J. Neurosci., 25, pp 213-23). Further, it is reported that TRPV1 knock-out mice show less anxiety-related behavior than their wild type littermates with no differences in locomotion (Marsch et al., 2007, J. Neurosci., 27(4), pp 832-9).
Based on the above-mentioned information, development of various TRPV1 antagonists is under way, and some patents and patent applications relating to TRPV1 antagonists under development were published. (Szallasi et al., 2007, Nat. Rev. Drug Discov., 6, pp 357-72; Appendino et al., 2006, Progress in Medicinal Chemistry, 44, pp 145-180; Rami et al., 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp 97-104; Correll et al., 2006, Expert Opin. Ther. Patents, 16, pp 783-795; Kyle et al., 2006, Expert Opin. Ther. Patents, 16, pp 977-996)
Compounds of the present disclosure, are useful for prophylaxis and treatment of diseases associated with the activity of TRPV1 (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369) including but not limited to, pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, dental pain, pelvic pain, migraine, bone cancer pain, mastalgia and visceral pain (Petersen et al., 2000, Pain 88, pp 125-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 56-62; Morgan et al., 2005, J. Orofac. Pain, 19, pp 248-60; Dinis et al., 2005, Eur. Urol., 48, pp 162-7; Akerman et al., 2004, Br. J. Pharmcol., 142, pp 1354-1360; Ghilardi et al., 2005, J. Neurosci., 25, 3126-31; Gopinath et al., 2005, BMC Womens Health, 5, 2-9); nerve-related diseases such as neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, and stroke (Park et al., 1999, Arch. Pharm. Res. 22, pp 432-434; Kim et al., 2005, J. Neurosci. 25(3), pp 662-671); diabetic neuropathy (Kamei et al., 2001, Eur. J. Pharmacol. 422, pp 83-86); fecal urgency; irritable bowel syndrome (Chan et al., 2003, Lancet, 361, pp 385-391); inflammatory bowel disease (Yiangou et al., 2001, Lancet 357, pp 1338-1339); gastrointestinal disorders such as gastro-esophageal reflux disease (GERD), stomach duodenal ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm., 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320); respiratory diseases such as asthma, chronic obstructive pulmonary disease, cough (Hwang et al., 2002, Curr. Opin. Pharmacol. pp 235-242; Spina et al., 2002, Curr. Opin. Pharmacol. pp 264-272; Geppetti et al., 2006, Eur. J. Pharmacol., 533, pp 207-214; McLeod et al., 2006, Cough, 2, 10); urinary incontinence (Birder et al., 2002, Nat. Neuroscience 5, pp 856-860); urinary bladder hypersensitiveness (Birder et al., 2001, PNAS, 98, pp 13396-13401); neurotic/allergic/inflammatory skin diseases such as psoriasis, pruritus, prurigo and dermatitis (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 217-222); irritation of skin, eye or mucous membrane (Tominaga et al., 1998, Neuron 21 pp 531-543); hyperacusis; tinnitus; vestibular hypersensitiveness (Balaban et al., 2003, Hear Res. 175, pp 165-70); cardiac diseases such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95, pp 1027-1034; Pan et al., 2004, Circulation 110, pp 1826-1831); haemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245(6), pp 964-70); hair growth-related disorders such as hirsutism, effluvium, alopecia (Bodo et al., 2005, Am. J. Patho. 166, pp 985-998; Biro et al., 2006, J. Invest. Dermatol. pp 1-4); rhinitis (Seki et al., 2006, Rhinology, 44, pp 128-34); pancreatitis (Hutter et al., 2005, Pancreas, 30, pp 260-5); cystitis (Dinis et al., 2004, J. Neurosci., 24, pp 11253-63; Sculptoreanu et al., 2005, Neurosci. Lett. 381, pp 42-6); vulvodynia (Tympanidis et al., 2004, Eur. J. Pain, 8, pp 12-33); psychiatric disorders such as anxiety or fear (Marsch et al., 2007, J. Neurosci., 27(4), pp 832-9).
Compounds that are related to VR1 activities are discussed e.g. in WO 02/61317, WO 02/090326, WO 02/16318, WO 02/16319, WO 03/053945, WO 03/099284, WO 03/049702, WO 03/049702, WO 03/029199, WO 03/70247, WO 04/07495, WO 04/72068, WO 04/035549, WO 04/014871, WO 04/024154, WO 04/024710, WO 04/029031, WO 04/089877, WO 04/089881, WO 04/072069, WO 04/111009, WO 05/03084, WO 05/073193, WO 05/051390, WO 05/049613, WO 05/049601, WO 05/047280, WO 05/047279, WO 05/044802, WO 05/044786, WO 06/097817, WO 06/098554, WO 06/100520, WO 06/101321, WO 06/102645, WO 06/103503, WO 06/111346, WO 06/101321, WO 06/101318, WO 06/1113769, WO 06/116563, WO 06/120481, WO 06/122250, WO 06/122799, WO 06/129164, WO 06/51378, WO 06/95263, WO 07/42906, WO 07/45462, WO 07/50732, WO 07/54474, WO 07/54480, WO 07/63925. WO 07/65663, WO 07/65888, WO 07/67619, WO 07/67710, WO 07/67711, WO 07/67756, WO 07/67757, WO07/63925, WO07/65662, WO07/65663, WO07/65888, WO07/69773, US20070149517, or US20070149513.
More specifically, WO 06/101321 and WO 06/101318 relate to VR1 modulators with a biphenyl partial structure. As a result of extensive and intensive studies, the present inventors have consequently synthesized novel compounds having VR1 antagonistic activity. Said new compounds have biphenylic structures, wherein one phenyl ring is substituted in para position to its attachment position to the rest of the molecule with a trifluoromethyl group or a fluoro, and has at least one additional substituent in ortho position (relative to said attachment position). Compared to the specific compounds disclosed in WO 06/101321 or WO 06/101318, which do not show this particular combination of features, the present compounds show remarkable improvement of their physicochemical characteristics, such as metabolic stability or pharmacokinetic profiles.
Therefore, it is an object of the present disclosure to provide novel compounds useful as a potent antagonist for a TRPV1, isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.